VCV000254998.57 - ClinVar

NM_000091.5(COL4A3):c.4484A>G (p.Gln1495Arg)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Benign/Likely benign

12 out of 16 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000091.5(COL4A3):c.4484A>G (p.Gln1495Arg)

Variation ID: 254998 Accession: VCV000254998.57

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q36.3 2: 227308920 (GRCh38) [ NCBI UCSC ] 2: 228173636 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 3, 2016	Jan 17, 2026	Dec 1, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000091.5:c.4484A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000082.2:p.Gln1495Arg	missense
NC_000002.12:g.227308920A>G
NC_000002.11:g.228173636A>G
NG_011591.1:g.149356A>G
LRG_230:g.149356A>G
LRG_230t1:c.4484A>G	LRG_230p1:p.Gln1495Arg
	Q01955:p.Gln1495Arg

... more HGVS ... less HGVS

Protein change

Q1495R

Other names

Canonical SPDI

NC_000002.12:227308919:A:G

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00260 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00219

The Genome Aggregation Database (gnomAD) 0.00573

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00728

1000 Genomes Project 0.00260

The Genome Aggregation Database (gnomAD) 0.00568

Trans-Omics for Precision Medicine (TOPMed) 0.00562

The Genome Aggregation Database (gnomAD), exomes 0.00629

Exome Aggregation Consortium (ExAC) 0.00677

The Genome Aggregation Database (gnomAD), exomes 0.00965

Links

ClinGen: CA2147562 UniProtKB: Q01955#VAR_001909 dbSNP: rs77964815 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
COL4A3		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	30	3303
MFF-DT	-	-	-	GRCh38	-	3169

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Aug 18, 2025	RCV000253369.16
not provided	Benign/Likely benign (7)	criteria provided, multiple submitters, no conflicts	Dec 1, 2025	RCV000960013.40
Alport syndrome	Benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV001136778.6
Kidney disorder	Likely benign (1)	criteria provided, single submitter	Apr 1, 2020	RCV002294102.4
Autosomal dominant Alport syndrome Autosomal recessive Alport syndrome Benign familial hematuria	Likely benign (1)	criteria provided, single submitter	Apr 6, 2022	RCV002494692.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	NOT SPECIFIED	PreventionGenetics, part of Exact Sciences Accession: SCV000302078.1 First in ClinVar: Oct 03, 2016 Last updated: Oct 03, 2016	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Mar 21, 2016) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711947.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Comment: show p.Gln1495Arg in exon 49 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 1.01% (671/66718) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs77964815). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 4

Benign (Apr 27, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Alport syndrome	Illumina Laboratory Services, Illumina Accession: SCV001296648.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (7) PubMed: 14871398‚ 27627812‚ 19525337‚ 14582039‚ 17216251‚ 12028435‚ 15880327 Comment: show This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Mar 30, 2021) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001554542.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Publications: PubMed (1) PubMed: 30661074 Comment: show Variant summary: COL4A3 c.4484A>G (p.Gln1495Arg) results in a conservative amino acid change located in the Collagen IV, non-collagenous domain (IPR001442) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0063 in 249324 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 3.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive phenotype (0.0019), strongly suggesting that the variant is benign. At-least one publication reports c.4484A>G with incomplete segregation, variable penetrance and non-informative phenotypes ranging from type-I diabetes, focal segmental glomerulosclerosis, microscopic hematuria, with normal renal function, normal hearing and no ocular abnormalities among in individuals in a family reportedly diagnosed with Alport Syndrome (Choi_2019). Furthermore, the variant did not segregate in an autosomal recessive manner in this family and the authors suggest a possible digenic association of this variant with another variant in the COL4A5 gene. No conclusions can be drawn from these data and this report does not provide unequivocal evidence supporting an association of this variant with Alport syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2)/likely benign (n=2). None of the submitters has cited the report utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Apr 01, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Kidney disorder	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002587147.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Apr 06, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Autosomal dominant Alport syndrome Hematuria, benign familial, 1 Autosomal recessive Alport syndrome	Fulgent Genetics, Fulgent Genetics Accession: SCV002798636.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Benign (Jan 30, 2019) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV000732312.3 First in ClinVar: Apr 09, 2018 Last updated: Mar 04, 2023	Comment: show This variant is associated with the following publications: (PMID: 17216251, 19525337, 14582039, 30661074, 12028435, 14871398, 30467950) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided (Autosomal recessive inheritance)	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005259038.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Observation: 1 Collection method: not provided Allele origin: germline Affected status: yes Observation 1 Collection method: not provided Allele origin: germline Affected status: yes

Benign (Jan 30, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001106958.7 First in ClinVar: Dec 17, 2019 Last updated: Feb 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Aug 18, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV006337004.1 First in ClinVar: Oct 05, 2025 Last updated: Oct 05, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Dec 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV002585864.25 First in ClinVar: Oct 22, 2022 Last updated: Jan 11, 2026	Comment: show COL4A3: BS1, BS2 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 11

Benign (Feb 14, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Not specified	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV007325320.1 First in ClinVar: Jan 17, 2026 Last updated: Jan 17, 2026	Publications: PubMed (5) PubMed: 12028435‚ 14871398‚ 30661074‚ 34426522‚ 9195222 Comment: show BS1, BS2, BS4 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 7

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001926900.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955462.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001970112.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (May 27, 2022) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Genetic Services Laboratory, University of Chicago Accession: SCV003839365.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Comment:

p.Gln1495Arg in exon 49 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 1.01% (671/66718) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs77964815).

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Comment:

Variant summary: COL4A3 c.4484A>G (p.Gln1495Arg) results in a conservative amino acid change located in the Collagen IV, non-collagenous domain (IPR001442) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0063 in 249324 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 3.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive phenotype (0.0019), strongly suggesting that the variant is benign. At-least one publication reports c.4484A>G with incomplete segregation, variable penetrance and non-informative phenotypes ranging from type-I diabetes, focal segmental glomerulosclerosis, microscopic hematuria, with normal renal function, normal hearing and no ocular abnormalities among in individuals in a family reportedly diagnosed with Alport Syndrome (Choi_2019). Furthermore, the variant did not segregate in an autosomal recessive manner in this family and the authors suggest a possible digenic association of this variant with another variant in the COL4A5 gene. No conclusions can be drawn from these data and this report does not provide unequivocal evidence supporting an association of this variant with Alport syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2)/likely benign (n=2). None of the submitters has cited the report utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Possible Digenic Disease in a Caucasian Family with COL4A3 and COL4A5 Mutations.	Choi M	Nephron	2019	PMID: 30661074
X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.	Savige J	PloS one	2016	PMID: 27627812
Screening for mutations in kidney-related genes using SURVEYOR nuclease for cleavage at heteroduplex mismatches.	Voskarides K	The Journal of molecular diagnostics : JMD	2009	PMID: 19525337
Nine novel COL4A3 and COL4A4 mutations and polymorphisms identified in inherited membrane diseases.	Rana K	Pediatric nephrology (Berlin, Germany)	2007	PMID: 17216251
The genetics of thin basement membrane nephropathy.	Rana K	Seminars in nephrology	2005	PMID: 15880327
COL4A3 mutations and their clinical consequences in thin basement membrane nephropathy (TBMN).	Wang YY	Kidney international	2004	PMID: 14871398
Autosomal recessive Alport's syndrome and benign familial hematuria are collagen type IV diseases.	Tazón Vega B	American journal of kidney diseases : the official journal of the National Kidney Foundation	2003	PMID: 14582039
COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome.	Longo I	Kidney international	2002	PMID: 12028435
The clinical spectrum of type IV collagen mutations.	Lemmink HH	Human mutation	1997	PMID: 9195222

Text-mined citations for rs77964815 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 17, 2026